Factors and pathways in the pathogenesis of Graves' ophthalmopathy and dermopathy were investigated using cultures of fibroblasts derived from retrobulbar tissue. Stimulation of hyaluronic acid (HA) synthesis in these cultures was considered to be analogous to in vivo changes of disease. Lymphocytes stimulated HA production and this process was mediated by cAMP and modulated by prostaglandins, particularly, E1. Prostaglandin inhibitors partially blocked the lymphocyte action. Efforts are made to purify and clarify the active factor in lymphocytes (a polypeptide). Preparations of bovine thyrotropin and luteinizing hormone also stimulate HA synthesis in the cultures, but the active factor in these pituitary extracts has not yet been isolated. It may not be either hormone in question. However, this factor differed in some important aspects from that found in lymphocytes. Thyroid fibroblasts produced less, and dermal fibroblasts more, HA than retrobulbar fibroblasts. Cultures of cells from thyroid and skin were less responsive to lymphocytes and pituitary hormone preparations than were the retrobulbar cells. Serum and LATS from patients with Graves' disease was ineffective in all cultures. No differences could be discerned in the metabolic features of fibroblasts derived from involved, uninvolved skin of patients with Graves' disease, and skin of patients without Graves' disease. No factor or stimulation response has been found to link the fibroblasts of the diverse tissues affected by Graves' disease.